Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL
Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL
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DOI：
10.4049/jimmunol.0901383
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发表时间：
2009-08-15
影响因子：
4.4
通讯作者：
Decker, Thomas
中科院分区：
文献类型：
--
作者：
Pilz, Andreas;Kratky, Wolfgang;Decker, Thomas
Y701上转录因子STAT-I的磷酸化调节亚细胞定位，而S727上的反式激活结构域的磷酸化增强转录活性。在这项研究中，我们研究了STAT-1的影响以及反式激活结构域磷酸化在TLR9依赖的免疫佐剂IC31存在下诱导多肽特异性CTL的重要性。STAT-1缺乏完全取消了免疫后的CTL诱导，而在携带S727磷酸受体突变的动物中，CTL诱导的CTL诱导明显减少。在缺乏I型干扰素(干扰素-I)受体的小鼠中发现了类似的CTL降低，而干扰素-γ缺陷的小鼠表现出与野生型对照相似的行为。这一发现表明，S727磷酸化的STAT-1支持依赖干扰素I的CTL诱导。在过继转移实验中，干扰素-I和S727-磷酸化的STAT-I对树突状细胞的激活和功能至关重要。去除T细胞特异性干扰素-I受体的小鼠没有表现出受损的CTL反应。与观察到的CTL发育情况不同，S727磷酸化的STAT-1在体外和转移到RAG缺陷小鼠后都抑制了初始CD8(+)T细胞的增殖。综上所述，我们的数据揭示了S727磷酸化的STAT-1对树突状细胞成熟的双重作用，作为诱导CTL活性和T细胞自主控制激活诱导或稳态增殖的先决条件。免疫学杂志，2009,183：2286-2293。
Phosphorylation of transcription factor STAT-I on Y701 regulates subcellular localization whereas phosphorylation of the transactivating domain at S727 enhances transcriptional activity. In this study, we investigate the impact of STAT-1 and the importance of transactivating domain phosphorylation on the induction of peptide-specific CTL in presence of the TLR9-dependent immune adjuvant IC31. STAT-1 deficiency completely abolished CTL induction upon immunization, which was strongly reduced in animals carrying the mutation of the S727 phospho-acceptor site. A comparable reduction of CTL was found in mice lacking the type I IFN (IFN-I) receptor, whereas IFN-gamma-deficient mice behaved like wild-type controls. This finding suggests that S727-phosphorylated STAT-1 supports IFN-I-dependent induction of CTL. In adoptive transfer experiments, IFN-I- and S727-phosphorylated STAT-I were critical for the activation and function of dendritic cells. Mice with a T cell-specific IFN-I receptor ablation did not show impaired CTL responses. Unlike the situation observed for CTL development S727-phosphorylated STAT-1 restrained proliferation of naive CD8(+) T cells both in vitro and following transfer into Rag-deficient mice. In summary, our data reveal a dual role of S727-phosphorylated STAT-1 for dendritic cell maturation as a prerequisite for the induction of CTL activity and for T cell autonomous control of activation-induced or homeostatic proliferation. The Journal of Immunology, 2009, 183: 2286-2293.